title: CEP biomarkers as potential tools for monitoring therapeutics.
abstract: BACKGROUND
  Carboxyethylpyrrole (CEP) adducts are oxidative modifications derived from docosahexaenoate-containing lipids that are elevated in ocular tissues and plasma in age-related macular degeneration (AMD) and in rodents exposed to intense light. The goal of this study was to determine whether light-induced CEP adducts and autoantibodies are modulated by pretreatment with AL-8309A under conditions that prevent photo-oxidative damage of rat retina. AL-8309A is a serotonin 5-HT1A receptor agonist.
  
  
  METHODS
  Albino rats were dark adapted prior to blue light exposure. Control rats were maintained in normal cyclic light. Rats were injected subcutaneously 3x with 10 mg/kg AL-8309A (2 days, 1 day and 0 hours) before light exposure for 6 h (3.1 mW/cm(2), λ=450 nm). Animals were sacrificed immediately following light exposure and eyes, retinas and plasma were collected. CEP adducts and autoantibodies were quantified by Western analysis or ELISA.
  
  
  RESULTS
  ANOVA supported significant differences in mean amounts of CEP adducts and autoantibodies among the light + vehicle, light + drug and dark control groups from both retina and plasma. Light-induced CEP adducts in retina were reduced ~20% following pretreatment with AL-8309A (n = 62 rats, p = 0.006) and retinal CEP immunoreactivity was less intense by immunohistochemistry. Plasma levels of light-induced CEP adducts were reduced at least 30% (n = 15 rats, p = 0.004) by drug pretreatment. Following drug treatment, average CEP autoantibody titer in light exposed rats (n = 22) was unchanged from dark control levels, and ~20% (p = 0.046) lower than in vehicle-treated rats.
  
  
  CONCLUSIONS
  Light-induced CEP adducts in rat retina and plasma were significantly decreased by pretreatment with AL-8309A. These results are consistent with and extend previous studies showing AL-8309A reduces light-induced retinal lesions in rats and support CEP biomarkers as possible tools for monitoring the efficacy of select therapeutics.
authors.affiliation: Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America ; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America ; Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Kutralanathan
authors.initials: K
authors.lastname: Renganathan
authors.forename: Jiayin
authors.initials: J
authors.lastname: Gu
authors.forename: Mary E
authors.initials: ME
authors.lastname: Rayborn
authors.forename: John S
authors.initials: JS
authors.lastname: Crabb
authors.forename: Robert G
authors.initials: RG
authors.lastname: Salomon
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Collier
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kapin
authors.forename: Carmelo
authors.initials: C
authors.lastname: Romano
authors.forename: Joe G
authors.initials: JG
authors.lastname: Hollyfield
authors.forename: John W
authors.initials: JW
authors.lastname: Crabb
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism; D008027:Light / Q000009:adverse effects; D008268:Macular Degeneration / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D011758:Pyrroles / Q000097:blood / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D012160:Retina / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D011758:Pyrroles; D004281:Docosahexaenoic Acids